SNAT7 regulates mTORC1 via macropinocytosis

  • Proc Natl Acad Sci U S A. 2022 May 17;119(20):e2123261119. doi: 10.1073/pnas.2123261119.
Delong Meng  1  2  3 ,  Qianmei Yang  1  2  3 ,  Mi-Hyeon Jeong  1  2  3 ,  Adna Curukovic  1  2  3 ,  Shweta Tiwary  1  2  3 ,  Chase H Melick  1  2  3 ,  Tshering D Lama-Sherpa  1  2  3 ,  Huanyu Wang  1  2  3 ,  Mariela Huerta-Rosario  2 ,  Greg Urquhart  1  2  3 ,  Lauren G Zacharias  4 ,  Cheryl Lewis  2 ,  Ralph J DeBerardinis  4  5 ,  Jenna L Jewell  1  2  3
Affiliations
  • 1. Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390.
  • 2. Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390.
  • 3. Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390.
  • 4. Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390.
  • 5. Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390.
PMID: 35561222 DOI: 10.1073/pnas.2123261119
Abstract

Mammalian target of rapamycin complex 1 (mTORC1) senses Amino acids to control cell growth, metabolism, and Autophagy. Some Amino acids signal to mTORC1 through the Rag GTPase, whereas glutamine and asparagine activate mTORC1 through a Rag GTPase-independent pathway. Here, we show that the lysosomal glutamine and asparagine transporter SNAT7 activates mTORC1 after extracellular protein, such as albumin, is macropinocytosed. The N terminus of SNAT7 forms nutrient-sensitive interaction with mTORC1 and regulates mTORC1 activation independently of the Rag GTPases. Depletion of SNAT7 inhibits albumin-induced mTORC1 lysosomal localization and subsequent activation. Moreover, SNAT7 is essential to sustain KRAS-driven pancreatic Cancer cell growth through mTORC1. Thus, SNAT7 links glutamine and asparagine signaling from extracellular protein to mTORC1 independently of the Rag GTPases and is required for macropinocytosis-mediated mTORC1 activation and pancreatic Cancer cell growth.

Keywords
SNAT7; mTOR; macropinocytosis.